Drug delivery using liposomes relies on cell uptake of the liposome by fusion or phagocytosis. Unfortunately, stabilized liposomes capable of specific cell targeting in vivo are resistant to these uptake mechanisms. A solution to this impasse is to couple molecular recognition of the target to the release of liposome contents. (Fyles and Zeng, Chem. Commun. 2295-2296 [1996]). The introduction of carriers capable of molecular recognition into liposomes that contain a drug of interest in the inner compartment of the liposomes introduces the potential of controlled release of the drug over a period of time. This approach to drug release has been used with other carriers in cancer chemotherapy. (See, Papahadjopoulos and Gabizon, Liposomes as Tools in Basic Research and Industry, J. A. Phillippot Ed., 1995).
The development of carriers that can recognize and transport common aminoacids as well as specific physiologically important molecules, such as the catecholamines and neurotransmitters, is in its infancy. Pioneering studies by Lehn and Cram have examined the transport of ammonium salts of aminoacids under acidic conditions across organic solvent membranes. (Behr and Lehn, J. Am. Chem. Soc. 95:6108 [1973]; Newcomb et al., J. Am. Chem. Soc. 101:7367 [1979]). The transport of hydrophobic aminoacids from aqueous solution at the isoelectric point across a CHCl.sub.3 solution that contained a Kemp's triacidacridine 2:1 condensate has been reported. (Rebek et al., J. Am. Chem. Soc. 109:2432 [1987]. The transport of phenylalanine in a neutral pH transport system, through chloroform membranes by cooperative ditopic interactions between the aminoacid, arylboronic acids and crown ethers has also been reported. (Reetz et al., J. Am. Chem. Soc. 116:11588-11589 [1994]). A similar system but with the boronic acids covalently attached to crown ethers was found effective in ditopic facilitated transport of catecholamines across bulk and polymer supported membranes. (Paugam et al., J. Am. Chem. Soc. 118:9820-9825 [1996]). A neutral bifunctional receptor that contains calix[4]phosphate and an appended uranyl salphen unit was found effective in the simultaneous transport of anions and cations (Rudkevich et al., J. Am. Chem. Soc. 116:6124-6125 [1995]. A ditopic receptor, that consists of a macrotricyclic quaternary ammonium unit bridged via a xylyl bridge to an aza crown ether, has been reported to interact with co-aminocarboxylates. (Schmidtchen, J. Org. Chem. 51:5161 [1986]). However, none of these are effective in transporting zwitterions at any significant rate.
Complexes of crown-ether functionalized planar multidentate complexes have been reported, which include derivatives of salicylideneimines, porphyrins and phthalocyanines. See e.g., Gok et al., Synth. React. Inorg. Met-Org. Chem. 27:331-345 [1997]; Karabocek et al., Polyhedron 16:1771-1774 [1997]; Gul et al., Synth. React. Inorg. Met-Org Chem. 16:871-884 [1986]; Van Staveren, et. al., J. Am. Chem. Soc. 110:4994 [1988]; Sessler et al., New J. Chem. 16:541-544 [1992]; Sielcken et al., Recl. Trav. Chim. Pays-Bas, 109:425 [1990]; Gasyna et al., J. Chem. Soc. Dalton Trans. 2397 [1989]; Sielcken et al., J. Am. Chem. Soc. 109:4261 [1987]; Kobayashi and Lever, J. Am. Chem. Soc. 109:7433[1987]; Kobayashi and Nishiyama, J. Chem. Soc. Chem. Commun. 1462 [1986]; Lehn, Pure and Appl. Chem. 50:871-892 [1978]; Can and Bek.ang.roglu, J. Chem. Soc. Dalton Trans. 2831-2835 [1988]). Furthermore, a number of carriers have been reported that contain crown ethers and transport cations, particularly alkali metal ions, across artificial membranes. (See e.g., Bitter et al., Bio-Organic Heterocycles Synthetic, Physical Organic and Pharmacological Aspects, Plas et al., ed., pp.397-400 [1984]; Kobuke and Yamamoto, Bioorg. Chem. 18:283-290 [1990]; Hamilton and Kaler, J. Membr. Sci. 54:259-269 [1990]; Darwish and Uchegbu, Int. J. Pharm. 159:207-213 [1997]; Grandjean Chem. Phys. Lipids 41:309-314 [1986]). However, none of these carriers are capable of interacting at more than one site, and none of them are effective in transporting zwitterions at any significant rate.
Crown ether-based bola-amphiphiles have also been reported. (See e.g., Munoz et al., J. Am. Chem. Soc. 115:1705-1711 [1993]; Munoz et al., J. Chem. Soc. Chem. Commun. 520-522 [1992]; Fyles and Zeng, Chem. Commun. 2295-2296 [1996]). The term "bola-amphiphiles" was first termed by Fuhrhop et al. to refer to several hydrophobic derivatives of succinic acid in which two polar headgroups are linked covalently by a hydrophobic, saturated hydrocarbon skeleton. (Fuhrhop et al., Advances in Supramolecular Chemistry Volume 2, Gokel, ed., pp. 25-63). Bola-amphiphiles often remain extended when dispersed in water and form monolayer lipid membrane vesicles known as bola-amphisomes. However, the bola-amphiphiles described by Munoz are themselves used as building blocks of liposomes. As such, they are immobile and do not serve as carriers for the transport of molecules. Although their crown ether appendices are capable for transport of metal ions, these crown ethers are unable to transport zwitterions.
Thus, there remains a need in the art for development of carriers that can recognize and transport common aminoacids as zwitterions, as well as specific physiologically important molecules, such as catecholamines and neurotransmitters (i.e., .gamma.-aminobutyric acid, serotonin noradrenaline, etc.). In addition, there remains a need in the art for the development of carriers that can be incorporated within liposome membranes for use in drug delivery systems.